Vincristine and concomitant azole therapy in pediatric acute lymphoblastic leukemia patients - a pharmacokinetic study

Vincristine (VCR) is an important component in the treatment of acute
lymphoblastic leukemia (ALL) in children. Proper dosing of vincristine is
required to maximize disease control while avoiding toxicity. Peripheral and
autonomic neuropathies are the most common side effects which can be
life-threatening. Vincristine pharmacokinetics are time- and dose-dependent and
considerable intra- and interpatient variation have previously been reported.
Vincristine is predominantly metabolized in the liver by the cytochrome P450
(CYP) 3A family of enzymes and eliminated by an efflux pump, P-glycoprotein
(P-gp). Inhibition of CYP3A4 by several drugs, such as azole antifungals, could
increase vincristine exposure and potentiate the side effects caused by
vincristine. Since in paediatric oncology patients azoles are increasingly
being used for prophylaxis and treatment of fungal infections, guidelines for
the co-administration of vincristine and azole therapy are necessary. The
azoles used for antifungal prophylaxis are itraconazole, voriconazole and
fluconazole. Several case reports suggest that co-administration of azoles and
vincristine lead to increased toxicity, but this has not been studied
specifically. It is not known whether these side-effects are related to a
higher exposure of vincristine, and to what extent this exposure is increased.
Information of the increase in plasma levels of vincristine during concomitant
azole therapy may lead to evidence-based dosing guidelines for the effective
and safe co-administration of these drugs, assuming that lower dose-levels of
vincristine are needed.

Primary objective:

To assess vincristine pharmacokinetics during concomitant azole therapy, which
is given in the context of standard treatment (hence this concerns an
observational and not an intervention study)


Secondary objectives:

- To evaluate the (neuro) toxicity of the combination of vincristine and azole
therapy in relation to the pharmacokinetics of both vincristine and azole
- To evaluate the (genetic) factors contributing to intrapatient variability in
vincristine pharmacokinetics and dynamics (e.g. toxicity)

A prospective, non-randomised multicentre study will be performed with patients
treated at the Pediatric Oncology departments of the Emma Childrens* Hospital
in Amsterdam, the Erasmus MC- Sophia Childrens* Hospital Rotterdam and the
Radboud University in Nijmegen for treatment for acute lymphoblastic leukemia
(ALL). The patients will be enrolled either on treatment with vincristine or
on treatment with vincristine and concomitant azole therapy. The study will
take place during Induction phase or Intensification phase for MR patients in
the DCOG-ALL protocol. To study the effect of the concomitant azole therapy on
the pharmacokinetics of vincristine a population based pharmacokinetic model
will be used.

Extra blood sampling in pediatric oncology patients gives minimal burden, since
regular blood sampling is obtained during the treatment process for ALL
patients. Blood sampling will be done using the existing vascular access ports
and the volume of blood will be 10 x 2.5 ml, 1 x 5 ml and 8 x 0.5 ml.
Manipulation of the vascular port will minimally increase the risk of
infection. The study needs to be performed in pediatric patients since ALL is
most common in this population and during the treatment of ALL concomitant
azole prophylaxe is used in the prevention of systemic infections during
neutropenia.